Protein folding is a process of supramolecular assembly that suffers unavoidable competition from alternative processes including misfolding to dead-end products and intermolecular association that may lead to aggregation. Yet, in order to perform their normal functions most proteins must fold correctly in challenging and complex cellular environments. In vivo, the processes that compete with folding can cause major physiological problems both because a protein cannot function if it does not adopt its native fold and also because the side-products of misfolding are potentially toxic to cells. Protein misfolding and its attendant consequences are implicated in a growing number of diseases, including cystic fibrosis, serpinopathies, and a number of neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's. Cells commit substantial resources to facilitate protein folding in complex in vivo environments and to minimize risks of misfolding. Central to how cells cope with the challenges of protein folding are the molecular chaperones and degradation enzymes that together comprise a protein homeostasis network. However, the ability of protein homeostasis networks to cope with proteins that are prone to misfolding (due either to their intrinsic properties, or mutations, or aberrant production) can be exceeded, and it is this situation that underlies many pathologies. The research in this MIRA application seeks to elucidate the interplay between biophysical properties of protein folding and the mechanisms of protein homeostasis networks through two overarching projects: 1) a combined computational modeling and experimental interrogation of protein homeostasis networks in E. coli and in eukaryotic cellular compartments, and 2) structure-function studies of the Hsp70 family of molecular chaperones, which play central roles in protein homeostasis networks in all kingdoms of life. The knowledge and insights gained from this research will shed light on how in-cell protein folding energy landscapes are remodeled by protein homeostasis networks. The understanding and insights provided by this research will help guide future efforts to develop therapeutic strategies to treat protein misfolding-associated diseases.